Project Abstract Multiple Sclerosis (MS) is an autoimmune disorder characterized by inflammation, demyelination, and neurodegeneration. Despite wide symptomatic variability, gray matter (GM) atrophy has consistently emerged as a strong indicator of clinical disability. In fact, evidence suggests progressive loss of GM correlates with disability and cognitive dysfunction better than many other magnetic resonance imaging biomarkers of MS, including enhancing lesions and lesion burden. While 40-70% of patients experience cognitive decline over the course of disease, there is no treatment on the market that can halt the progression of GM atrophy or cognitive decline. Current treatment options are primarily designed to reduce inflammation and have had only modest success at slowing GM atrophy in MS. Treatment with the sex hormone estriol has been shown to reduce relapses and preserve GM in both MS and in experimental autoimmune encephalomyelitis (EAE), its most commonly used mouse model. Recently, in a clinical trial with female MS patients, estriol treatment was shown to reduce GM atrophy and improve performance in cognitive testing. The mechanisms underlying the neuroprotective effects of estriol remain unclear. Understanding how estriol is working to preserve GM tissue may lead to the development of better neuroprotective therapies for patients with MS and potentially other neurodegenerative conditions. Our preliminary data suggest that estriol treatment in EAE reduces GM atrophy and neuronal loss in the cerebral cortex and prevents axonal transection in the spinal cord. Further, we have found that axonal transection in the spinal cord is correlated with GM volume almost exclusively in the motor and sensory motor cortices. In this proposal, I will utilize the EAE mouse model to 1) identify regions where estriol treatment preserves GM volume and what changes in pathology are associated with GM preservation, 2) characterize the effect of estriol on oxidative stress in mitochondria, and 3) identify genes differentially expressed in cortical neurons from estriol-treated animals. This project will provide invaluable information about how estriol provides neuroprotection in GM and will highlight potential targets for future neuroprotective therapies.